chr17-81868810-T-TG

Variant names:

• chr17-81868810-T-TG
• rs757131763
• NM_004309.6:c.*65dupC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004309.6(ARHGDIA):​c.*65dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 437,842 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (3 hom.)
• Consequence: ARHGDIA NM_004309.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0640
• Publications: 0 publications found

Genes affected

ARHGDIA (HGNC:678): (Rho GDP dissociation inhibitor alpha) This gene encodes a protein that plays a key role in the regulation of signaling through Rho GTPases. The encoded protein inhibits the disassociation of Rho family members from GDP (guanine diphosphate), thereby maintaining these factors in an inactive state. Activity of this protein is important in a variety of cellular processes, and expression of this gene may be altered in tumors. Mutations in this gene have been found in individuals with nephrotic syndrome, type 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ARHGDIA Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 8

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0029 (1150/396892) while in subpopulation EAS AF = 0.0189 (220/11656). AF 95% confidence interval is 0.0168. There are 3 homozygotes in GnomAdExome4. There are 570 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIA	NM_004309.6	c.*65dupC		3_prime_UTR_variant	Exon 6 of 6	ENST00000269321.12	NP_004300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGDIA	ENST00000269321.12	c.*65dupC		3_prime_UTR_variant	Exon 6 of 6	1	NM_004309.6	ENSP00000269321.7

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 74 AN: 40890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00793

Gnomad SAS AF: 0.00296

Gnomad FIN AF: 0.000480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000696 AC: 142 AN: 204026 AF XY: 0.000659

Gnomad AFR exome AF: 0.000229

Gnomad AMR exome AF: 0.0000387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00170

Gnomad FIN exome AF: 0.000159

Gnomad NFE exome AF: 0.000894

Gnomad OTH exome AF: 0.000208

GnomAD4 exome AF: 0.00290 AC: 1150 AN: 396892 Hom.: 3 Cov.: 35 AF XY: 0.00263 AC XY: 570 AN XY: 216800

African (AFR) AF: 0.000782 AC: 9 AN: 11504

American (AMR) AF: 0.0000344 AC: 1 AN: 29104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10586

East Asian (EAS) AF: 0.0189 AC: 220 AN: 11656

South Asian (SAS) AF: 0.00165 AC: 82 AN: 49560

European-Finnish (FIN) AF: 0.000280 AC: 7 AN: 24968

Middle Eastern (MID) AF: 0.000370 AC: 1 AN: 2704

European-Non Finnish (NFE) AF: 0.00334 AC: 803 AN: 240252

Other (OTH) AF: 0.00163 AC: 27 AN: 16558

GnomAD4 genome AF: 0.00181 AC: 74 AN: 40950 Hom.: 0 Cov.: 32 AF XY: 0.00193 AC XY: 39 AN XY: 20244

African (AFR) AF: 0.000284 AC: 3 AN: 10558

American (AMR) AF: 0.000525 AC: 2 AN: 3810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 990

East Asian (EAS) AF: 0.00794 AC: 16 AN: 2016

South Asian (SAS) AF: 0.00296 AC: 4 AN: 1352

European-Finnish (FIN) AF: 0.000480 AC: 1 AN: 2082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.00250 AC: 48 AN: 19204

Other (OTH) AF: 0.00 AC: 0 AN: 550

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.064
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757131763; hg19: chr17-79826686; COSMIC: COSV99482611; COSMIC: COSV99482611;